Process of preparing aldehydo acylated ribose, and product thereof



Patented Apr. 1, 1941 UNITED STATES PATENT: OFFICE PROCESS OF PREPARINGALDEKYDO AC- ca,N.

YLATED'RIBOSE, AND PRODUCT THERE- more to Charles Pfizer & Company,Brooklyn, N. Y., a corporation of New Jersey No Drawing.

Application December 16,1939, I Serial No. 309,700 I 6 Claims. (Cl.260210) This invention relates to a process for the preparation ofaldehydo acylated ribose from arabonic acid, and to the intermediateproducts developed by the process. Hitherto ribose has been known onlyin its lactol form, produced, for example, by Emil Fischer's method ofreducing ribonolactone with sodium amalgam. We have now found'that bythe following sequence of reactions, it is possible to make asubstituted aldehydoribose which is most suitable for syntheticpurposes.

In practice it is convenient to use calcium arabonate as the startingmaterial. Arabonic acid is set free from this salt by treatment with thecalculated amount of sulfuric acid and epimerlzed *by heating withpyridine. Ribonolactone is recovered according to the method of Fischerand Piloty (Ber. 24: 4214, 1891). If d-ribonolactone in absolute ethylalcohol is treated with dry ammonia, it gives d-ribonamide, small plates"of melting point 136-437 C. Initial rotation in aqueous solutionRibonamide, by treatment with acid anhydrides or chlorides and pyridine,is converted to the corresponding derivative with its hydroxyl groupsaliphatic or aromatic acids may he used, but an- I hydrides are ingeneral preferable to chlorides, and for many purposes acetic anhydrideis best suited.

The tetraacylated ribonamide is converted to tetraacylated ribonic acidby means of nitrous anhydride according to the method of Hurd and Sowden(J. Am. Chem. Soc. 60: 235-7, 1938). This isconverted to the acidchloride by treatment with phosphorus pentachloride. The tetraacylatedribonyl chloride is then reduced to tetraacyl ribose by the method .ofRosenmund and Zetsche (Ber. 51: 585 and 595, 1918) using hydrogen with apalladium catalyst, precipitated on barium sulfate.

- While calcium arabonate, ribonic acid and its lactone, andl-ribonamide are of course known in the art, there is no evidence thateither aldehydo acylated ribose or any of the tetraacylated intermediatecompounds produced in our process have ever before existed. Levene andTipsou (J. Biol. Chem. 92: 110) produced a tetraacetyl ribose, but

this could not have been in the aldehyde form,.

since it is known in the art that aldehydopentose acetates do not formby direct acetylation. 'Ihe '---'distinction from our product is furtheremphasized by the physical constants, which Levene and TlD on found tobe: Melting point 110 and' [a ,;'-52

(in chloroform).

mples of the steps of our process are as follows:

Preparation of tetraacetyl-fibonamide.1000 grams of d-ribonamide isadded gradually with stirring to a mixture of 3500 cc. pyridine and 3500cc. acetic anhydride. The temperature tends to rise rapidly owing toheat of reaction. This is prevented by outside cooling and agitation,since at elevated temperatures there is a considerable darkening of thematerial and the yield is substantially reduced. It is preferable tomaintain the temperature below 40 C. After standing over night, thepyridine and acetic acid are distilled oil and the tetraacetylribonamideproduct crystallized from methyl alcohol. (Melting point l23- 0.;

[a],26.3 for c, 5% in methyl alcohol.)

When propion ic anhydride is used instead of acetic anhydride, thepreferable amount is about 4500 cc. The tendency'toward temperature riseis not so marked, but it is still advisable to apply sufficient coolingeffect to keep the solution below 40 C. The tetrapropionyl ribonamidecrystallized from methyl alcohol has a melting point of 123-124 C. and

. dium bicarbonate solution and precipitated with hydrochloric acid. Themelting point of the resulting tetraacetyl-d-ribonic acid is 138-139 C.;

[a],'--27.3 at c, 5% in acetic acid; a e-29.5"

-at c, 5% in ethyl acetate.

If tetrapropionyl-d-ribonamide is used as the starting material, theamount is about 117 grams instead of 100 grams, but the process is notsubstantially different.

Preparation of tetraacetul-d-ribonul chloride.- 300 grams oftetraacetyl-d-ribonic acid is dissolved in 500 cc. of dry CH0]: andreacted with 225 grams of PCls. At the end of this reaction, thechloroform and phosphorus oxychloride are distilled. The residue oftetraacetyl-d-ribonyl chloride is crystallized from dry xylene and has amelting point of 75 C. I

Preparation of tetraacetul-d-ribose.-Hydrogen is bubbled into a boilingmixture of 200 grams of tetraacetyl-d-rlbonyl chloride and 75 grams of5% Pd--BaSO4 catalyst in 500 cc. of dry xylene under reflux. HCl isdriven off and when HCl evolution stops, the reaction mixture isfiltered. Tetraacetyl-d-ribose crystallizes and is collected andrecrystallized from dry xylene and has a melting point of 98-99 C. and

ribose from ribonam'lde, comprising acylation of ribonamide by heatingwith pyridene and a member selected from the group consisting oi! theanhydrides and chlorides of the lower fatty acids. converting theresulting acylated amide to the corresponding acylated acid by theaction of nitrous anhydride, treating the tetraacylated prodnot withphosphorus pentachloride to form the corresponding acylated acidchloride, and reducing the latter with hydrogen at atmospheric pressurein the presence of a palladium catalyst to form the correspondingaldehydo acylated ribose.

2. As new products, ribonyl derivatives of the formula AOHzC(CHOA)rCO-R, where A represents an acyl radical selected from the groupconsisting of the lower fatty acids and It represents any member or thegroup consisting of Mir, OH, Cl and H.

8. As a new product, tetrapropionyl ribonamide.

4. As a new product, tetraacetyl ribonamide.

5. As a new product, tetraacetyl ribonic acid.

6. As a new product, aldehyde tetraacetyl ribose.

RICHARD PASTERNACK. ELLIS V. BROWN.

DISCLAIM-ER '2,237,263.Richard Pestermwk, Brooklyn, and Ellis v. Brown,Jamaica, N. Y.

PROCESS OF PREPARING ALDEHYDO ACYLA'PED RIBOSE, AND PRODUCT THEREOF.Patent dated April 1, 1941. Disclaimer filed May 12, 1942, by theinventors; the assignee, Charles Pfizer (E: Company, consenting.

Hereby enter this disclaimer to claims 2, 4, and 5 of said LettersPatent.

" [Ofieial Gazette June 9, 1942.]

